Angiogenesis is a process of generating new blood vessels from pre-existing ones, and is a vital process in normal innate defense mechanisms such as wound healing and inflammation, and biological phenomenon and early-stage development.
Further, angiogenesis is very important in terms of clinical application as well as basic medicine, considering its clinical therapeutic effect obtained by blocking angiogenesis in the diseases like cancer, diabetic retinopathy, psoriasis, or rheumathritis, and therapeutic effect obtained by inducing angiogenesis in the diseases derived from the lack of new vessels such as cardiac infarction or ischemic limb. Given this, studies in the molecular and cellular mechanisms of angiogenic process are considered to be a prototype that can have a variety of clinical applications.
Meanwhile, the angiogenic process involves a series of sequential steps including decomposition of basement membrane of vessels by proteolytic enzyme, tube formation of endothelial cells that constitute vessel walls by re-construction of blood vessels by migration, proliferation and differentiation of the endothelial cells and generation of new capillary vessels.
The angiogenic process is strictly regulated by a variety of negative and positive regulatory factors, because if not regulated normally, this can exacerbate various diseases including cancer, rheumathritis, or diabetic retinopathy. Abnormal angiogenesis is particularly known as playing a vital role in the growth and metastatis of tumor, considering, first, its operation of supplying nutrients and oxygen needed for the growth and proliferation of tumor, and second, the new capillary vessels which invade into the tumor and provide tumor cells a chance to get into the blood circulation system, thereby enabling the tumor cells to spread all over the body.
Accordingly, studies about the angiogenic mechanisms and development of new matters that can inhibit angiogenesis have gained increasing attention in the prevention and treatment of various diseases including cancer, and recently, the studies about angiogenic inhibitor have been accelerated as the pre-clinical experiments on animal tumor models and the clinical studies confirmed that the angiogenic inhibition can effectively inhibit the growth and development of tumor and prolong patients' lives. Further, such angiogenic inhibitor is particularly considered to be promising in the anticancer therapy, because, first, angiogenic inhibitor can be used universally in all types of solid tumors, second, while the conventional anticancer chemo-therapy has toxicity on the bone marrow cells and stomach system cells with relatively faster cell cycle due to its principle of targeting fast growth of cancer cells, the angiogenic inhibitor has relatively less side effects even for a long period of administration, third, it is possible to suppress many cancer cells through inhibition of one blood vessel cell, because one vessel cell can supply nutrients and oxygen to hundreds of cancer cells, and fourth, while the conventional anticancer therapy needs release of anticancer agent out of the vessel to influence the cancer cells, the angiogenic inhibitor directly contacts the endothelial cells to thus have facilitated drug delivery.
Theory about existence of the endothelial progenitor cells (EPC) circulating in the blood of an adult has been reported a hundred years ago, which was characterized in 1997 by Dr. Isner group and published for the first time in the Science. After that, many study groups have found evidences that indicate the existence of the endothelial progenitor cells (EPC) in the peripheral blood, bone marrow and umbilical cord blood. Particularly, it was confirmed that the EPC in the peripheral blood was derived from bone marrow, and it was reported that when the EPC cultured ex vivo was injected in vivo, the transplanted cells were incorporated into a site of angiogenesis in the ischemia animal models and xenograft tumor animal models, thereby contributing to angiogenesis. Studies have been actively undertaken about various growth factors and cytokine involved in the EPC migration.
The above shows changes in the paradigm of the angiogenesis in adults, and recently, it has been understood that the bone marrow EPC, as well as endothelial cells sprouting from the pre-existing blood vessels contribute to the angiogenesis.
However, while the therapeutic availability of EPC for ischemic tissue has been confirmed and clinical benefit has been expected. identification and characterization of EPCs have not been studied sufficiently. Markers that can distinguish from endothelial cells have not been developed, and far more has to be known about regulation of EPC differentiation.
Meanwhile, approximately 200 angiogenic inhibitors have been developed so far, which can be mainly characterized into four mechanisms of: lowering activity of a specific vascular growth factor; suppressing growth or inducing death of vascular endothelial cells; suppressing the action of indirect factors that regulate the vascular growth factor or the endothelial cell survival factors; and increasing the activity of the angiogenesis inhibitor present in body. The angiogenesis inhibitors such as angiostatin, endostatin, PK5, and prothrombin kringle 2 are particularly widely known.
Conventionally, study about how to inhibit signal transduction triggered by vascular endothelial growth factor (VEGF) for the purpose of inhibiting angiogenesis has been continued. In this case, angiogenesis appears to be suppressed in the early stage, but the vessels are formed more aggressively thereafter by acquisition of resistance. Considering the resistance and possible other disadvantageous side effects in vivo of the above-mentioned angiogenesis inhibitors, development of a new angiogenesis inhibitor with novel mechanism is necessary, which can resolve the problems occurring in the prior arts and also effectively suppress the angiogenesis.